This invention relates to a process for preparing organoboron compounds which involves reacting an appropriately substituted organic compound with a substituted borane. In particular the invention relates to the synthesis of aryl or vinyl borates using disubstituted monohydroboranes and related species. These organoborates, and their corresponding boronic acids, are useful reactants in organic coupling reactions. They are particularly useful in the synthesis of new and known organic molecules and have application in the synthesis of pharmaceuticals, pesticides and other useful organic compounds. The compounds represent useful intermediates and building blocks for organic synthesis and are useful in combinatorial chemistry.
Processes for forming covalent bonds between organic compounds, both inter- and intra-molecular, are of particular importance to the synthetic organic chemist. Many such reactions are known, each requiring its own special reaction conditions, solvents, catalysts, activating groups etc. Some known types of coupling reactions involving olefinic moieties include the Michael reaction and reactions described in the following references: Transition Metals in the Synthesis of Complex Organic Molecules (L. S. Hegedus, University Science Books, 1994, ISBN 0-935702-28-8); Handbook of Palladium Catalysed Organic Reactions (J. Malleron, J. Fiaud and J. Legros, Academic Press, 1997, ISBN 0-12-466615-9); Palladium Reagents and Catalysts (Innovations in Organic Synthesis by J. Tsuji, John Wiley and Sons, 1995, ISBN 0-471-95483-7); and N. Miyuara and A. Suzuki, Chem Rev. 1995, 95, 2457-2483.
Catalysts of palladium, its complexes and its salts are well recognised for activation of Cxe2x80x94H bonds towards coupling reactions. In this regard the Heck reaction of an alkene with an aryl or vinyl halide in the presence of palladium derivatives has been the subject of intensive study. Other Group VIII metal catalysts, such as platinum, have also been used to activate such carbon bonds.
The success of the Heck reaction depends to a large extent on the substrates and the reaction conditions. When two xcex2-hydrogens are present in the alkene the reaction generally leads to the formation of the (E)-alkenes which are often contaminated with the corresponding (Z)-alkenes.
Although alkene borates (alkenylborates) can be reacted with a variety of organic molecules to give coupled products via the formation of new carbon-carbon bonds (See for example the references above) the process for the preparation of the alkenylborates by the commonly used hydroboration reaction of alkynes is limited because of the difficulties that are encountered through the lack of regiochemistry and/or chemoselectivity (such as the reduction of a number of different functional groups) (See N. Miyuara and A. Suzuki, Chem Rev. 1995, 95, 2457-2483). Improved methodologies are thus required for the synthesis of alkene borates.
Substituted bi- and tri-aryl compounds are of great interest to the pharmaceutical and agrochemical industries. A great number of these compounds have been found to possess pharmaceutical activity, while others have been found to be useful pesticides. There is also interest from the polymer industry in polymers prepared by the linking together of aromatic ring compounds.
Conventional methods for covalently linking aromatic rings, such as by reaction of an appropriate Grignard reagent, involve harsh conditions and are not suitable for aromatic rings with active hydrogen containing substituents. Substituents with active hydrogen atoms also can become involved in unwanted side reactions leading to undesirable products. Such substituents need to be protected prior to reaction. Boronic acid derivatives required for the Suzuki reaction are traditionally synthesized through highly reactive organonietallic intermediates.
In view of the severity of the reaction conditions the range of substituents which could be present during the formation of the boronic acid derivatives was considerably limited, and the range of useful reaction media (solvents) was restricted.
It has now been found that aryl and alkene borates can be synthesised from particular substituted olefinic or aromatic ring compounds under mild conditions and in the presence of a range of substituents. This process overcomes or at least alleviates one or more of the limitations encountered in the use of the conventional hydroboration methodology and is fundamentally different, in the case of the preparation of alkene borates, in that the starting material is an alkene and not an alkyne.
Accordingly the invention provides a process for the synthesis of an alkene or aryl borate which comprises reacting:
(i) an olefinic compound having a halogen or halogen-like substituent in a vinylic substitution position, or
(ii) an aromatic ring compound having a halogen or halogen-like substituent in a ring substitution position, said aromatic ring compound also having at least one substituent selected from the group consisting of hydroxy, amino, imino, acetyleno, carboxy (including carboxylato), carboximidyl, sulfo, sulfinyl, sulfinimidyl, sulfinohydroximyl, sulfonimidyl, sulfondiimidyl, sulfonohydroximyl, sultamyl, phosphinyl, phosphinimidyl, phosphonyl, dihydroxyphosphanyl, hydroxyphosphanyl, phosphono (including phosphonato), hydrohydroxyphosphoryl, allophanyl, guanidino, hydantoyl, ureido, and ureylene
with a disubstituted monohydroborane, in the presence of a Group 8-11 metal catalyst and a suitable base, such that a borane residue is introduced at the substitution position.
For convenience, the reaction described above will be referred to as the xe2x80x9cboronation reactionxe2x80x9d.
The term xe2x80x9cdisubstituted monohydroboranexe2x80x9d refers to a monoboron compound having two non-hydrogen substituents and one hydrogen substituent.
The term xe2x80x9cborane residuexe2x80x9d refers to a disubstituted monohydroborane moiety after breakage of the Bxe2x80x94H bond. An example of a borane residue is the moiety (RO)2Bxe2x80x94 where R is as defined below.
This process is fundamentally different from the conventional hydroboration processes in that substitution occurs rather than addition. Accordingly a completely different mechanism is involved.
According to conventional hydroboration processes, alkyl 3 and alkeneboronic esters 5 are prepared from the corresponding alkenes 2 and alkynes 4 as shown below with pinacol borane: 
These reactions formally add one hydrogen and a boronic acid ester across the respective substrates. No base is required and although the reactions may be catalysed by transition metal species these are not essential. With monoalkyl alkynes the reactions yield the (E)-pinacol (1-alkenyl)boronates 5 as the major stereoisomer. The other two isomers 5a and 5b are difficult to obtain using this methodology. 
However the present invention provides a convenient route to these difficult to obtain isomers. Instead of addition across a double bond as described above the present invention results in the replacement of a halide or halogen-like substituent in the vinylic position with a borane residue. Accordingly the location of the borane residue in the product is governed by the location of the halide.
Aromatic compounds do not hydroboronate with the use of the reagent 1.
The process according to the present invention also provides advantages over other processes for activating carbon atoms towards coupling reactions. According to the present process it is possible to synthesise a wide range of substituted aryl and alkene borates, without the need for the prior protection of a wide variety of functional groups, including active hydrogen functionalities.
It is possible to generate the disubstituted monohydroborane in situ by reaction of a borane with an appropriate alcohol or amine. In a particularly preferred embodiment the borane ester so prepared can be used without isolation in the boronation reaction. This process can be used to generate esters, as well as ester/amides or diamides. This process surprisingly allows the generation and reaction of disubstituted monohydroboranes which cannot be isolated in their pure form or which readily disproportionate. Some amine species may give adducts of borane that are not sufficiently reactive to give the desired H2 elimination and these reactions may require more vigorous conditions.
Preferably the borane used to generate the disubstituted monohydroborane is a polyhydroborane. Examples of polyhydroboranes which may be useful according to this aspect of the invention include sulphide and ether adducts of BH3. Examples of such adducts include dialkylsulphide adducts, such as BH3.S(CH3)2, ether adducts, such as BH3.THF, and cyclic sulphide adducts such as BH3.1,4-oxathiane. Preferably the adduct is BH3.S(CH3)2.
As mentioned above the aryl and alkene borates so produced may be coupled to other organic compounds having a halogen or halogen-like substituent by reacting the borate with the organic compound in the presence of a Group 8-11 metal catalyst and a suitable base.
Accordingly the invention provides a process for covalently coupling organic compounds which comprises:
(A) preparing an alkene or aryl borate by reacting
(i) an olefinic compound having a halogen or halogen-like substituent in a vinylic coupling position, or
(ii) an aromatic ring compound having a halogen or halogen-like substituent in a ring coupling position, said aromatic ring compound also having at least one substituent selected from the group consisting of hydroxy, amino, imino, acetyleno, carboxy (including carboxylato), carboximidyl, sulfo, sulfinyl, sulfinimidyl, sulfinohydroximyl, sulfonimidyl, sulfondiimidyl, sulfonohydroximyl, sultamyl, phosphinyl, phosphinimidyl, phosphonyl, dihydroxyphosphanyl, hydroxyphosphanyl, phosphono (including phosphonato), hydrohydroxyphosphoryl, allophanyl, guanidino, hydantoyl, ureido, and ureylene,
with a disubstituted monohydroborane, in the presence of a Group 8-11 metal catalyst and a suitable base, such that borane residue is introduced at said coupling position; and
(B) reacting the alkene or aryl borate with an organic compound having a halogen or halogen-like substituent at a coupling position in the presence of a Group 8-11 metal catalyst and a suitable base, whereby the olefinic or aromatic ring compound is coupled to the organic compound via a direct bond between the respective coupling positions.
This process allows for the preparation of symmetrical and asymmetrical products by selection of appropriate reactants.
It is especially convenient to conduct this process in a single pot without isolating the aryl or alkene borate, however it has been found that the presence of unreacted disubstituted monohydroborane can interfere with the coupling step, resulting in the formation of unwanted by-products.
Accordingly, after preparation of the aryl or alkene borate, excess disubstituted monohydroborane may be decomposed by adding a suitable proton donor compound such as water, alcohols, acids or mixtures thereof. The ease with which the excess disubstituted monohydroborane can be destroyed is of specific advantage in the formation of asymmetrically coupled products by the xe2x80x98one potxe2x80x99 method. In particular, the formation of asymmetrically coupled compounds, to the exclusion of symmetrically coupled compounds, requires that there is no excess disubstituted monohydroborane present in the reaction solution when organic compound having a halogen or halogen-like substituent in a coupling position is added to the preformed boronic acid ester.
In the case of olefinic and aromatic ring compounds having halogen or halogen substituents in vinylic or ring coupling positions respectively it is possible to prepare symmetrical products in a number of ways.
In one embodiment the disubstituted monoborane is contacted with two equivalents of olefinic or aromatic ring compound to form an alkene or aryl borate, which borate reacts with the remaining halogenated compound to form the coupled product. According to this embodiment the covalent coupling comprises a covalent bond between the respective coupling positions of two molecules of the halogenated compound. A second base may be added and/or the reaction mixture may be heated after the formation of the aryl or alkene borate to catalyse or promote the coupling reaction. Alternatively oxidative coupling may be used, such as described in Katharine H. Smith, Eva M. Campi, W Roy Jackson, Sebastian Marcuccio, Charlotta G. M. Naeslund and Glen B. Deacon Synlett January 1997, 131-132.
The symmetrical product may also be prepared by first preparing the aryl or alkene borate and then adding further halogenated compound to the reaction medium. As with the previous method it may be necessary to add base and/or heat to the reaction to promote the coupling reaction. If, instead of adding the same halogenated compound to the reaction medium, a different halogenated compound is added, then unsymmetrical products can be obtained. Destruction of the excess monohydroborane before addition of the organic compound is advantageous. Adding a second solvent in which the base is soluble is also of advantage when the base is not soluble in the solvent used for the borate synthesis.
The terms xe2x80x9colefinicxe2x80x9d and xe2x80x9colefinic compoundxe2x80x9d as used herein refer to any organic compound having at least one carbon to carbon double bond which is not part of an aromatic or pseudo aromatic system. The olefinic compounds may be selected from optionally substituted straight chain, branched or cyclic alkenes; and molecules, monomers and macromolecules such as polymers and dendrimers, which include at least one carbon to carbon double bond. Examples of suitable olefinic compounds include but are not limited to ethylene, propylene, but-1-ene, but-2-ene, pent-1-ene, pent-2-ene, cyclopentene, 1-methylpent-2-ene, hex-1-ene, hex-2-ene, hex-3-ene, cyclohexene, hept-1-ene, hept-2ene, hept-3-ene, oct-1-ene, oct-2-ene, cyclooctene, non-1-ene, non-4-ene, dec-1-ene, dec-3-ene, buta-1,3-diene, penta-1,4-diene, cyclopenta-1,4-diene, hex-1, diene, cyclohexa-1,3-diene, cyclohexa-1,4-diene, cyclohepta-1,3,5-triene and cycloocta-1,3,5,7-tetraene, each of which may be optionally substituted. Preferably the straight chain branched or cyclic alkene contains between 2 and 20 carbon atoms. The olefinic compounds may be xcex1,xcex2-unsaturated carbonyl compounds, or conjugated dienes. The term xe2x80x9cconjugated dienesxe2x80x9d as used herein refers to any compound capable of acting as a diene in a Diels-Alder reaction.
In one embodiment the olefinic compound (i) is a compound of formula I 
where R1, R2 and R3 are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, acyl, arylalkyl and heteroarylalkyl (each of which may be optionally substituted), cyano, isocyano, formyl, carboxyl, nitro, halo, alkoxy, alkenoxy, aryloxy, benzyloxy, haloalkoxy, haloalkenyloxy, haloaryloxy, nitroalkyl, nitroalkenyl, nitroalkynyl, arylamino, diarylamino, dibenzylamino, alkenylacyl, alkynylacyl, arylacyl, acylamino, diacylamino, acyloxy, allylsulphonyloxy, arylsulphenyloxy, heterocycloxy, arylsulphenyl, carboalkoxy, carboaryloxy, alkylthio, benzylthio, acylthio, sulphonamide, sulfanyl, sulfo, carboxy (including carboxylato), carbamoyl, carboximidyl, sulfinyl, sulfinimidyl, sulfinohydroximyl, sulfonimidyl, sulfondiimidyl, sulfonohydroximyl, sulfamyl, phosphorous containing groups (including phosphinyl, phosphinimidyl, phosphonyl, dihydroxyphosphanyl, hydroxyphosphanyl, phosphone (including phosphonato) and hydrohydroxyphosphoryl), alkoxysilyl, silyl, alkylsilyl, alkylalkoxysilyl, phenoxysilyl, alkylphenoxysilyl, alkoxyphenoxy silyl and arylphenoxy silyl.
The term xe2x80x9caromatic ring compound(s)xe2x80x9d as used herein refers to any compound which includes or consists of one or more aromatic or pseudoaromatic rings. The rings may be carbocyclic or heterocyclic, and may be mono or polycyclic ring systems. Examples of suitable rings include but are not limited to benzene, biphenyl, terphenyl, quaterphenyl, naphthalene, tetrahydronaphthalene, 1-benzylnaphthalene, anthracene, dihydroanthracene, benzanthracene, dibenzanthracene, phenanthracene, perylene, pyridine, 4-phenylpyridine, 3-phenylpyridine, thiophene, benzothiophene, naphthothiophene, thianthrene, furan, pyrene, isobenzofuram, chromene, xanthene, phenoxathiin, pyrrole, imidazole, pyrazole, pyrazine, pyrimidine, pyridazine, indole, indolizine, isoindole, purine, quinoline, isoquinoline, phthalazine, quinoxaline, quinazoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, phenazine, isothiazole, isooxazole, phenoxazine and the like, each of which may be optionally substituted. The term xe2x80x9caromatic ring compound(s)xe2x80x9d includes molecules, and macromolecules, such as polymers, copolymers and dendrimers which include or consist of one or more aromatic or pseudoaromatic rings. The term xe2x80x9cpseudoaromaticxe2x80x9d refers to a ring system which is not strictly aromatic, but which is stablized by means of delocalization of n electrons and behaves in a similar manner to aromatic rings. Examples of pseudoaromatic rings include but are not limited to furan, thiophene, pyrrole and the like.
As used herein the term xe2x80x9corganic compound having a halogen or halogen-like substituent at a coupling positionxe2x80x9d refers to any organic compound having a carbon to halogen or carbon to halogen-like substituent bond at a position where coupling to the olefinic or aromatic compound is desired. The organic compound may be aliphatic, olefinic, allylic, acetylenic, aromatic, polymeric or dendritic. The organic compound may be an olefinic compound as defined above or part of such an olefinic compound. The organic compound may have one or more, preferably between 1 and 6, halogen or halogen-like substituents at coupling positions.
The term xe2x80x9ccoupling positionxe2x80x9d as used herein refers to a position on an organic compound at which coupling to another organic compound is desired. A coupling position on a carbon atom which is part of an olefinic carbon to carbon bond is also referred to as a xe2x80x9cvinylic coupling positionxe2x80x9d. Each olefinic compound or organic compound may have one or more, preferably between 1 and 6, coupling positions.
The term xe2x80x9csubstitution positionxe2x80x9d as used herein refers to a position on an olefinic or aromatic ring compound at which substitution with a borane residue is desired. Each organic compound may have one or more, preferably between 1 and 6, substitution positions. In an aromatic compound it is preferred that the substitution position is directly on the ring and with an olefinic compound it is preferred that the substitution position is at a vinylic position. If the organic compound is a polymer or a dendrimer it may have many substitution positions.
As used herein, the term xe2x80x9cleaving groupxe2x80x9d refers to a chemical group which is capable of being displaced by a boronic acid residue. Suitable leaving groups are apparent to those skilled in the art and include halogen and halogen-like substituents, as well as ester groups.
In this specification xe2x80x9coptionally substitutedxe2x80x9d means that a group may or may not be further substituted with one or more groups selected from alkyl, alkenyl, alkynyl, aryl, halo, haloalkyl, haloalkenyl, haloalkynyl, haloaryl, hydroxy, alkoxy, alkenyloxy, aryloxy, benzyloxy, haloalkoxy, haloalkenyloxy, haloaryloxy, isocyano, cyano, formyl, carboxyl, nitro, nitroalkyl, nitroalkenyl, nitroalkynyl, nitroaryl, nitroheterocyclyl, amino, alkylamino, dialkylamino, alkenylamino, alkynylamino, arylamino, diarylamino, benzylamino, imino, alkylimine, alkenylimine, alkynylimino, arylimino, benzylimino, dibenzylamino, acyl, alkenylacyl, alkynylacyl, arylacyl, acylamino, diacylamino, acyloxy, alkylsulphonyloxy, arylsulphenyloxy, heterocyclyl, heterocycloxy, heterocyclamino, haloheterocyclyl, alkylsulphenyl, arylsulphenyl, carboalkoxy, carboaryloxy mercapto, alkylthio, benzylthio, acylthio, sulphonamido, sulfanyl, sulfo and phosphorus-containing groups, alkoxysilyl, silyl, alkylsilyl, alkylalkoxysilyl, phenoxysilyl, alkylphenoxysilyl, alkoxyphenoxy silyl and arylphenoxy silyl.
The olefinic compound (i) must include at least one halogen or halogen-like substituent at a vinylic coupling position to enable reaction with the disubstituted monohydroborane.
Similarly the organic compound must have at least one halogen or halogen-like substituent at a coupling position to enable reaction with the alkene borate intermediate. Preferred halogen substituents include I, Br and Cl. The reactivity of chloro substituted compounds can be increased by selection of appropriate ligands on the Group 8-11 metal catalyst. The terms xe2x80x9chalogen-like substituentxe2x80x9d and xe2x80x9cpseudo-halidexe2x80x9d refer to any substituent which, if present, may undergo substitution with a disubstituted monohydroborane in the presence of a Group 8-11 metal catalyst and base to give an aryl or alkene borate, or if present on an organic compound may undergo substitution with an aryl or alkene borate to give a coupled product. Examples of halogen-like substituents include triflates and mesylates, diazonium salts, phosphates and those described in Palladium Reagents and Catalysts (Innovations in Organic Synthesis by J. Tsuji, John Wiley and Sons, 1995, ISBN 0-471-95483-7).
The process according to the present invention is especially suitable for the formation of aryl and alkene borates from aromatic or olefinic compounds containing active hydrogen containing substituents. The term xe2x80x9cactive hydrogen containing substituentxe2x80x9d as used herein refers to a substituent which contains a reactive hydrogen atom. Examples of such substituents include but are not limited to hydroxy, amino, imino, acetyleno, carboxy (including carboxylato), carboximidyl, sulfo, sulfinyl, sulfinimidyl, sulfinohydroximyl, sulfonimidyl, sulfondiimidyl, sulfonohydroximyl, sultamyl, phosphinyl, phosphinimidyl, phosphonyl, dihydroxyphosphanyl, hydroxyphosphanyl, phosphono (including phosphonato), hydrohydroxyphosphoryl, allophanyl, guanidino, hydantoyl, ureido, and ureylene. Of these substituents it is particularly surprising that the reaction can be conducted with hydroxy and amino substituents. Additional disubstituted monohydroboranes may be required for those compounds containing substituents with active hydrogens. An additional advantage of the process of this invention is its ability to solubilise starting material in situ.
While the present invention allows the reaction of compounds with active hydrogen containing substituents without prior protection, it is also possible, and sometimes advantageous, to do so. The use of protecting groups can reduce the amount of disubstituted monohydroborane required to perform the boronation reaction. Examples of suitable hydroxy protecting groups are described in Protective Group in Org Synthesis, T. W. Green and P Wuts J Wiley and Son 2nd Edition 1991. In a particularly preferred embodiment the active hydrogen compound is reacted with a borane compound, such as one of the polyhydroboranes described above, for example with a phenolic compound having halogen or halogen-like substituent. The triester of the phenol can be formed using a borane compound, such as borane methylsulphide adduct, which ester can be used as the reactant in a subsequent boronation reaction. If the pinacol or other ester of the arylboronic acid species is not sought in the first instance (these can be made by subsequent esterification/transesterification) the diester of the borane with the phenol can be made and then used as the boronation reagent. As an alternative, a borate ester can be partially or completely transesterified with, for example, a phenolic aryl halide and this species can be used as a reactant in the subsequent boronation reaction. Boric acid can also be used to remove the active hydrogen by formation of the triester, with for example, an aryl halide containing an hydroxy (phenolic) group.
This concept can be extended to other reactants containing active hydrogen substituents, although it should be noted that borane reactants generally do not react with the active hydrogen groups of primary or secondary amides.
One method for preparing olefinic compounds having a halogen-like substituent in a vinylic substitution position is by the conversion of a carbonyl group with a xcex2-hydrogen into a trapped enol form, this enol being useful in the process of the present invention. This is achieved by trapping the enol with a mesylate or triflate group or the like. This enol is then reacted with the disubstituted monohydroborane in the presence of a Group 8-11 metal catalyst and a suitable base to form the vinylic boronate.
It has also been unexpectedly found that the induction time required for the reaction of the olefinic or aromatic ring compound with the disubstituted monohydroborane can be substantially reduced by the addition of a promoter.
Accordingly in a further aspect of the present invention there is provided a process for the synthesis of an alkene or aryl borate which comprises reacting:
(i) an olefinic compound having a halogen or halogen-like substituent in a vinylic substitution position, or
(ii) an aromatic ring compound having a halogen or halogen-like substituent in a ring substitution position,
with a disubstituted monohydroborane, in the presence of a Group 8-11 metal catalyst, a suitable base and a promoter such that a borane residue is introduced at the substitution position.
The promoter may be any suitable compound or reagent which is capable of increasing the rate of reaction between an olefinic or aromatic ring compound and a disubstituted monohydroborane in the presence of a Group 8-11 metal catalyst and a suitable base. The promoter may be an amide. Examples of suitable amide promoters include p-iodoacetanilide, acetanilide, acetamide and N-methylacetamide.
The use of a promoter is particularly advantageous in the reaction of aromatic ring compounds having electron withdrawing groups, or in the reaction of olefinic compounds.
It has also been found that the catalyst activity can be increased, prior to its use in the reaction, by treatment with a suitable base or mixture of bases. Organic amines are suitable bases for this treatment. Besides the enhancement of the reaction rate this catalyst treatment has the further advantage that side product formation is reduced. In particular, this catalyst treatment reduces the extent of substrate dehalogenation, increases the yield of the required organic boronic acid derivative and reduces the amount of the arylboronic acid derivative in which the aryl group is derived from a ligand on the catalyst.
It is of advantage to carry out the activation of the catalyst with base(s) before the contacting of the disubstituted monohydroborane with the catalyst. This activation may be achieved by heating the catalyst with base(s). The base may be the amine used to promote the boronation reaction. The temperature and reaction time required for activation will vary with catalyst composition, the nature of the base and also the solvent. The catalyst should be treated to such an extent that there is little or no induction time in the subsequent boronation reaction. For some catalysts there is a colour change as activation occurs. The activated catalyst may be stored for subsequent use in the boronation reaction or can be used immediately following activation, without isolation from the base with which it is heated.
According to this aspect of the invention there is provided a process for the synthesis of an alkene or aryl borate which comprises reacting
(i) an olefinic compound having a halogen or halogen-like substituent in a vinylic substitution position, or
(ii) an aromatic ring compound having a halogen or halogen-like substituent in a ring substitution position,
with a disubstituted monohydroborane, in the presence of a Group 8-11 metal catalyst and a suitable base such that a borane residue is introduced at the substitution position,
wherein the Group 8-11 metal catalyst is activated by treatment with an organic amine prior to contacting of the disubstituted monohydroborane with the catalyst.
In the above definitions, the term xe2x80x9calkylxe2x80x9d, used either alone or in compound words such as xe2x80x9calkenyloxyalkylxe2x80x9d, xe2x80x9calkylthioxe2x80x9d, xe2x80x9calkylaminoxe2x80x9d and xe2x80x9cdialkylaminoxe2x80x9d denotes straight chain, branched or cyclic alkyl, preferably C1-20 alkyl or cycloalkyl. Examples of straight chain and branched alkyl include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, amyl, isoamyl, sec-amyl, 1,2-methylpropyl, 1,1-dimethyl-propyl, hexyl, 4-methylpentyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 1,2,2,-trimethylpropyl, 1,1,2-trimethylpropyl, heptyl, 5-methoxyhexyl, 1-methylhexyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 4,4-dimethylpentyl, 1,2-dimethylpentyl, 1,3-dimethylpentyl, 1,4-dimethyl-pentyl, 1,2,3,-trimethylbutyl, 1,1,2-trimethylbutyl, 1,1,3-trimethylbutyl, octyl, 6-methylheptyl, 1-methylheptyl, 1,1,3,3-tetramethylbutyl, nonyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-methyl-octyl, 1-, 2-, 3-, 4- or 5-ethylheptyl, 1-, 2- or 3-propylhexyl, decyl, 1-, 2-, 3-, 4-, 5-, 6-, 7- and 8-methylnonyl, 1-, 2-, 3-, 4-, 5- or 6-ethyloctyl, 1-, 2-, 3- or 4-propylheptyl, undecyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-methyldecyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-ethylnonyl, 1-, 2-, 3-, 4- or 5-propylocytl, 1-, 2- or 3-butylheptyl, 1-pentylhexyl, dodecyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9- or 10-methylundecyl, 1-, 2-, 3-, 4-, 5-, 6-, 7- or 8-ethyldecyl, 1-, 2-, 3-, 4-, 5- or 6-propylnonyl, 1-, 2-, 3- or 4-butyloctyl, 1-2-pentylheptyl and the like. Examples of cyclic alkyl include mono- or polycyclic alkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl and the like.
The term xe2x80x9calkoxyxe2x80x9d denotes straight chain or branched alkoxy, preferably C1-20 alkoxy. Examples of alkoxy include methoxy, ethoxy, n-propoxy, isopropoxy and the different butoxy isomers.
The term xe2x80x9calkenylxe2x80x9d denotes groups formed from straight chain, branched or cyclic alkenes including ethylenically mono-, di- or poly-unsaturated alkyl or cycloalkyl groups as previously defined, preferably C2-20 alkenyl. Examples of alkenyl include vinyl, allyl, 1-methylvinyl, butenyl, iso-butenyl, 3-methyl-2-butenyl, 1-pentenyl, cyclopentenyl, 1-methylcyclopentenyl, 1-hexenyl, 3-hexenyl, cyclohexenyl, 1-heptenyl, 3-heptenyl, 1-octenyl, cyclooctenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 1-decenyl, 3-decenyl, 1,3-butadienyl, 1-4,pentadienyl, 1,3-cyclopentadienyl, 1,3-hexadienyl, 1,4-hexadienyl, 1,3-cyclohexadienyl, 1,4-cyclohexadienyl, 1,3-cycloheptadienyl, 1,3,5-cycloheptatrienyl and 1,3,5,7-cyclooctatetraenyl.
The term xe2x80x9calkynylxe2x80x9d denotes groups formed from straight chain, branched or cyclic alkyne including those structurally similar to the alkyl and cycloalkyl groups as previously defined, preferably C2-20 alkynyl. Examples of alkynyl include ethynyl, 2-propynyl and 2- or 3-butynyl.
The term xe2x80x9cacylxe2x80x9d either alone or in compound words such as xe2x80x9cacyloxyxe2x80x9d, xe2x80x9cacylthioxe2x80x9d, xe2x80x9cacylaminoxe2x80x9d or xe2x80x9cdiacylaminoxe2x80x9d denotes carbamoyl, aliphatic acyl group and acyl group containing an aromatic ring, which is referred to as aromatic acyl or a heterocyclic ring which is referred to as heterocyclic acyl, preferably C1-20 acyl. Examples of acyl include carbamoyl; straight chain or branched alkanoyl such as formyl, acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 2,2-dimethylpropanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, heptadecanoyl, octadecanoyl, nonadecanoyl and icosanoyl; alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, t-pentyloxycarbonyl and heptyloxycarbonyl; cycloalkylcarbonyl such as cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl and cyclohexylcarbonyl; alkylsulfonyl such as methylsulfonyl and ethylsulfonyl; alkoxysulfonyl such as methoxysulfonyl and ethoxysulfonyl; aroyl such as benzoyl, toluoyl and naphthoyl; aralkanoyl such as phenylalkanoyl (e.g. phenylacetyl, phenylpropanoyl, phenylbutanoyl, phenylisobutylyl, phenylpentanoyl and phenylhexanoyl) and naphthylalkanoyl (e.g. naphthylacetyl, naphthylpropanoyl and naphthylbutanoyl; aralkenoyl such as phenylalkenoyl (e.g. phenylpropenoyl, phenylbutenoyl, phenylmethacryloyl, phenylpentenoyl and pheenylhexenoyl and naphthylalkenoyl (e.g. naphthylpropenoyl, naphthylbutenoyl and naphthylpentenoyl); aralkoxycarbonyl such as phenylalkoxycarbonyl (e.g. benzyloxycarbonyl); aryloxycarbonyl such as phenoxycarbonyl and napthyloxycarbonyl; aryloxyalkanoyl such as phenoxyacetyl and phenoxypropionyl; arylcarbamoyl such as phenylcarbamoyl; arylthiocarbamoyl such as phenylthiocarbamoyl; arylglyoxyloyl such as phenylglyoxyloyl and naphthylglyoxyloyl; arylsulfonyl such as phenylsulfonyl and napthylsulfonyl; heterocycliccarbonyl; heterocyclicalkanoyl such as thienylacetyl, thienylpropanoyl, thienylbutanoyl, thienylpentanoyl, thienylhexanoyl, thiazolylacetyl, thiadiazolylacetyl and tetrazolylacetyl; heterocyclicalkenoyl such as heterocyclicpropenoyl, heterocyclicbutenoyl, heterocyclicpentenoyl and heterocyclichexenoyl; and heterocyclicglyoxyloyl such as thiazolylglyoxyloyl and thienylglyoxyloyl.
The terms xe2x80x9cheterocyclicxe2x80x9d, xe2x80x9cheterocyclylxe2x80x9d and xe2x80x9cheterocyclxe2x80x9d as used herein on their own or as part of a term such as xe2x80x9cheterocyclicalkenoylxe2x80x9d, heterocycloxyxe2x80x9d or xe2x80x9chaloheterocyclylxe2x80x9d refer to aromatic, pseudo-aromatic and non-aromatic rings or ring systems which contain one or more heteroatoms selected from N, S, and O and which may be optionally substituted. Preferably the rings or ring systems have 3 to 20 carbon atoms. The rings or ring systems may be selected from those described above in relation to the definition of xe2x80x9caromatic ring compound(s)xe2x80x9d.
The term xe2x80x9carylxe2x80x9d as used herein on its own or as part of a group such as xe2x80x9chaloarylxe2x80x9d and xe2x80x9caryloxycarbonylxe2x80x9d refers to aromatic and pseudo-aromatic rings or ring systems composed of carbon atoms, optionally together with one or more heteroatoms. Preferably the rings or ring systems have between 3 and 20 carbon atoms. The rings or ring systems may be optionally substituted and may be selected from those described above in relation to the definition of xe2x80x9caromatic ring compound(s)xe2x80x9d.
Examples of suitable monohydroboranes include those of the formula (RX)2Bxe2x80x94H where each X is independently selected from O, S and NRxe2x80x3 where Rxe2x80x3 is H, an optionally substituted alkyl or optionally substituted aryl and each R is independently selected from optionally substituted alkyl and optionally substituted aryl or where xe2x80x94B(XR)2 represents a cyclic group of formula II 
where Rxe2x80x2 is optionally substituted alkylene, arylene or other divalent group comprising linked aliphatic or aromatic moieties and X is as defined above. Preferred disubstituted monohydroboranes are dialkoxy hydroboranes including 4,4-dimethyl-1,3,2-dioxaborinane, 4,4,6-trimethyl-1,3,2-dioxaborinane, 4,4,6,6-tetramethyl-1,3,2-dioxaborinane, 4,4dimethyl-1,3,2-dioxaborolane, 4,4,5-trimethyl-1,3,2-dioxaborolane, 4,4,5,5-tetramethyl-1,3,2-dioxaborolane, 4-phenyl-1,3,2-dioxaborinane, n-propanediolborane (1,3,2-dioxaborinane), 5,5-dimethyl-1,3,2-dioxaborinane, (4R,5R)-4,5-bis(1-methoxy-1-methylethyl)-1,3,2-dioxaborolane, (4S,5S)-4,5-bis(1-methoxy-1-methylethyl)-1,3,2-dioxaborolane, dinaphtho[2,1-d:1,2-f][1,3,2]dioxaborepine, (4R,5R)-3,4-dimethyl-5-phenyl-1,3,2-oxazaborolidine, (4S,5S)-3,4-dimethyl-5-phenyl-1,3,2-oxazaborolidine, (4R,5R)-3-isopropyl-4-methyl-5-phenyl-1,3,2-oxazaborolidine and (4S,5S)-3-isopropyl methyl-5-phenyl-1,3,2-oxazaborolidine. Some preferred disubstituted monohydroboranes which are novel and represent a further aspect of the invention are (4R,5R)-4,5-dimethyl-1,3,2-dioxaborolane, (4S,5S)-4,5-dimethyl-1,3,2-dioxaborolane, (4R,5R)-4,5-diphenyl-1,3,2-dioxaborolane, (4S,5S)-4,5-diphenyl-1,3,2-dioxaborolane, (4S)-4-(methoxymethyl)-1,3,2-dioxaborolane, (4R)-4-(methoxymethyl)-1,3,2-dioxaborolane, tetrahydro-3aH-cyclopenta[d][1,3,2]dioxaborole, 3-methyl-1,3,2-oxazaborolidine, (6R)-4,4,6-trimethyl-1,3,2-dioxaborinane, (6S)-4,4,6-trimethyl-1,3,2-dioxaborinane, hexahydro-1,3,2-benzodioxaborole, (4R,5R)-4,5-bis(methoxymethyl)-1,3,2-dioxaborolane, (4S,5S)-4,5-bis(methoxymethyl)-1,3,2-dioxaborolane, (4R,5R)-4,5-dicyclohexyl-1,3,2-dioxaborolane, (4S,5S)-4,5-dicyclohexyl-1,3,2-dioxaborolane, (5R)-4,4-dimethyl-5-phenyl-1,3,2-dioxaborolane, (5S)-4,4-dimethyl-5-phenyl-1,3,2-dioxaborolane, (4R)-4-phenyl-1,3-dioxa-2-boraspiro[4.4]nonane, (4S)-4-phenyl-1,3-dioxa-2-boraspiro[4.4]nonane, (4S,5S)-4,5-bis(1-methoxycyclopentyl)-1,3,2-dioxaborolane, (4R,5R)-4,5-bis(1-methoxycyclopentyl)-1,3,2-dioxaborolane, diisopropyl(4S,5S)-1,3,2-dioxaborolane-4,5-dicarboxylate, diisopropyl(4R,5R)-1,3,2-dioxaborolane-4,5-dicarboxylate, (1R,2S,6S,7S)-1,10,10-trimethyl-6-phenyl-3,5-dioxa-4-boratricyclo[5.2.1.02,6]decane, (1S,2R,6R,7R)-1,10,10-trimethyl-6-phenyl-3,5-boratricyclo[5.2.1.02,6]decane, (3aR)-3a-methyl-3,3-di(2-naphthyl)tetrahydro-3H-pyrrolo[1,2-c][1,3,2]oxazaborole, (3aS)-3a-methyl-3,3-di(2-naphthyl)tetrahydro-3H-pyrrolo[1,2-c][1,3,2]oxazaborole, (3aR)-3,3-di(2-naphthyl)tetrahydro-3H-pyrrolo[1,2-c][1,3,2]oxazaborole (3aS)-3,3-di(2-naphthyl)tetrahydro-3H-pyrrolo[1,2-c][1,3,2]oxazaborole, (4S,5S)-4,5-bis[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-1,3,2-dioxaborolane, (4R,5R)-4,5-bis[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-1,3,2-dioxaborolane, (2R)-2-{(4S,5S)-5-[(2R)-1,4-dioxaspiro[4.5]dec-2-yl]-1,3,2-dioxaborolanyl-4-yl}-1,4-dioxaspiro[4.5]decane, (2S)-2-{(4R,5R)-5-[(2S)-1,4-dioxaspiro[4.5]dec-2-yl]-1,3,2-dioxaborolan-4-yl}-1,4-dioxaspiro[4.5]decane, (4S,5S)-N4,N4,N5,N5-tetramethyl-1,3,2-dioxaborolane-4,5-dicarboxamide, (4R,5R)-N4,N4,N5,N5-tetramethyl-1,3,2-dioxaborolane-4,5-dicarboxamide, (1R,2R,6S,8R)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1 1.02,6]decane and (1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.02,6]decane.
Some of the hydroborane derivatives will be more readily amenable to subsequent hydrolysis than others and may allow for the use of milder reaction conditions. Furthermore, judicious choice of the hydroborane derivative used may facilitate control over the reaction products formed. The dioxyhydroborane derivatives may be made following the method of Tucker, C. E. et al, J. Org. Chem, 1992, 57, 3482-3485, Contreras, R. et al, Spectrochimica Acta 1984 40A 855 or Bello-Ramxc3xadrez, M. A., Rodrxc3xadguez Martxc3xadnez, M. E., and Flores-Parra, A., Heteroatom Chem., 1993, 4, 613. Other methods for the preparation of the hydroborane derivatives will be known to those in the art.
The present invention also provides a route to some chiral compounds. Chiral aryl and alkene borates may be prepared using chiral disubstituted monohydroboranes. If the chiral monohydroborane has an enantiomeric excess of one enantiomer over another, this can produce chiral aryl and alkene borates having a corresponding enantiomeric excess. The chirality of an aryl or alkene borate may also be transferred to a coupled product. Chiral products may also be achieved using chiral catalysts.
The term xe2x80x9cGroup 8-11 metal catalystxe2x80x9d as used herein refers to a catalyst comprising a metal of Groups 8-11 of the periodic table described in Chemical and Engineering News, 63(5), 27, 1985. Examples of such metals include Ni, Pt and Pd. Preferably the catalyst is a palladium catalyst, although analogous catalysts of other Group 8-11 metals may also be used.
Examples of suitable palladium catalysts include but are not limited to Pd3(dba)3, PdCl2, Pd(OAc)2, PdCl2(dppf)CH2Cl2, Pd(PPh3)4 and related catalysts which are complexes of phosphine ligands, (such as (Ph2P(CH2)nPPh2) where n is 2 to 5, P(o-tolyl)3, P(i-Pr)3, P(cyclohexyl)3, P(o-MeOPh)3, P(p-MeOPh)3, dppp, dppb, TDMPP, TTMPP, TMPP, TMSPP, 2-(di-t-butylphosphino)biphenyl, (R,R)-Me-DUPHOS, (S,S)-Me-DUPHOS, (R)-BINAP, (S)-BINAP, and related water soluble phosphines), related ligands (such as triarylarsine, triarylantimony, triarylbismuth), phosphite ligands (such as P(OEt)3, P(O-p-tolyl)3, P(O-o-tolyl)3, P(O-iPr)3, tris(2,4-di-t-butylphenyl)phosphite and other examples described in the STREM Catalogue No. 18 (Chemicals for Research: metals, inorganics and organometallics 1999-2001)) and other suitable ligands including those containing P and/or N atoms for coordinating to the palladium atoms, (such as for example pyridine, alkyl and aryl substituted pyridines, 2,2xe2x80x2-bipyridyl, alkyl substituted 2,2xe2x80x2-bipyridyl and bulky secondary or tertiary amines), and other simple palladium salts either in the presence or absence of ligands. The palladium catalysts include palladium and palladium complexes supported or tethered on solid supports, such as palladium on carbon, as well as palladium black, palladium clusters and palladium clusters containing other metals and palladium in porous glass as described in J. Li, A. W-H. Mau and C. R. Strauss, Chemical Communications, 1997, p1275. The same or different Group 8-11 metal catalysts may be used to catalyse different steps in the process. It can be an advantage to select a catalyst with ligands that cannot exchange aryl groups with the aromatic ring compound or that minimise this exchange.
The Group 8-11 metal catalyst may be a platinum complex. Examples of suitable platinum catalysts include but are not limited to Pt(dba)2, Pt(PPh3)2Cl2, PtCl2, Pt(OAc)2, PtCl2(dppf)CH2Cl2, Pt(PPh3)4 and related catalysts which are complexes of phosphine ligands, (such as (Ph2P(CH2)nPPh2) where n is 2 to 5, P(o-toly)3, P(i-Pr)3, P(cyclohexyl)3, P(o-MeOPh)3, P(p-MeOPh)3, dppp, dppb, TDMPP, TTMPP, TMPP, TMSPP, 2-(di-t-butylphosphino)biphenyl, (R,R)-Me-DUPHOS, (S,S)-Me-DUPHOS, (R)-BINAP, (S)-BINAP and related water soluble phosphines), related ligands (such as triarylarsine, triarylantimony, triarylbismuth), phosphite ligands (such as P(OEt)3, P(O-p-tolyl)3, P(O-o-tolyl)3, P(O-iPr)3, tris(2,4-di-t-butylphenyl)phosphite and other examples described in the STREM Catalogue No. 18 (Chemicals for Research: metals, inorganics and organometallics 1999-2001)) and other suitable ligands including those containing P and/or N atoms for coordinating to the platinum atoms, (such as for example pyridine, alkyl and aryl substituted pyridines, 2,2xe2x80x2-bipyridyl, alkyl substituted 2,2xe2x80x2-bipyridyl and bulky secondary or tertiary amines), and other simple platinum salts either in the presence or absence of ligands. The platinum catalysts include platinum and platinum complexes supported or tethered on solid supports, such as platinum on carbon, as well as platinum black, platinum clusters and platinum clusters containing other metals.
The Group 8-11 metal catalyst may also be selected from those described in U.S. Pat. No. 5,686,608. In certain reactions there are advantages in using ligands with altered basicity and/or steric bulk. Examples of suitable Ni catalysts include nickel complex, Raney nickel, nickel on carbon and nickel clusters or a nickel black. Preferred catalysts are those that readily undergo oxidative addition and reductive elimination. One skilled in the art would be able to select a suitable catalyst on this basis. Catalysts of palladium are preferred. The Group 8-11 metal catalyst may contain other metals.
Suitable catalysts also include metallocyclic compounds and compounds that can form metallocyclic species in situ in the reaction medium.
The catalysts according to the present invention may be prepared in situ. For example catalysts consisting of phosphine complexes of palladium can be prepared in situ by addition of a palladium (II) salt such as the acetate and the desired mono- or di-phosphine in a ratio such that the Pd/P atom ratio is approximately 1:2. Arsines, such as for example bis(diphenylarsino) ethane and the like can also be used in conjunction with Pd to make active catalysts for the boronation of aryl halide type species.
The process for preparing the boronates may be performed in any suitable solvent or solvent mixture. Examples of such solvents include lower alkyl esters of the lower aliphatic carboxylic acids, cyclic and the lower secondary and tertiary antines, amides of the lower aliphatic carboxylic acids and lower aliphatic secondary amines, aromatic or aliphatic hydrocarbons, acetonitrile, benzonitrile, ethers, polyethers, cyclic ethers, lower aromatic ethers, and mixtures thereof, including mixtures with other solvents.
Preferred solvents include n-heptane, DMA, DMSO, 1,2-dichlorethane, toluene, acetonitrile, dioxane, DME, diethyl ether, THF or mixtures thereof with other solvents. The addition of further disubstituted monoborane derivative may be useful when the solvents are not anhydrous.
The temperature at which each step of the process according to the invention is conducted will depend on a number of factors including the desired rate of reaction, solubility and reactivity of the reactants in the selected solvent, boiling point of the solvent, etc. The temperature of the reaction will generally be in the range of xe2x88x92100 to 250xc2x0 C. In a preferred embodiment the process is performed at a temperature between 0 and 120xc2x0 C., more preferably between 15 and 80xc2x0 C.
The term xe2x80x9csuitable basexe2x80x9d as used herein refers to a basic compound which, when present in the reaction mixture, is capable of catalysing, promoting or assisting reaction between reactants. The base may be suitable for promoting a single step, or more than one step, depending on the desired outcome of the reaction. For example a base may be chosen which promotes reaction between the olefinic or aromatic compound and the disubstituted monohydroborane, but which is not strong enough under the conditions used in the reaction to promote further reaction of the aryl or alkene borate with additional aryl or olefinic compound, or other organic compound. It is also preferable that a base is chosen which is soluble in the solvent to which it is added. Examples of bases which are suitable for promoting the reaction of the olefinic or aromatic compound with the disubstituted monohydroborane include secondary amines, tertiary amines, aliphatic cyclic amines and amines bearing a second or more hetero atom. Some of these bases may be used in conjunction with a phase transfer reagent, such as for example tetraalkylammonium salts or the crown ethers.
Examples of bases suitable for catalysing reaction of the olefinic or aromatic compounds with the disubstituted monoborane, without generally catalysing the further reaction of the aryl or alkene intermediate include triethylamine, and other N-bases.
Bases that can be used to activate the catalyst prior to use in the reaction are preferably chosen from secondary amines, tertiary amines, aromatic amines, aliphatic cyclic amines and amines bearing a second or more hetero atom.
Examples of bases that can be used to promote the catalytic activity of the catalyst by treatment with the base(s) prior to use in the reaction include but are not limited to triethylamine, 2,6-dimethylpiperidine and N-methylpiperidine.
Examples of compounds suitable for decomposing excess disubstituted monohydroborane include water, alcohols and acids.
As used herein the terms xe2x80x9calkene boratexe2x80x9d and xe2x80x9caryl boratexe2x80x9d refer to the products of the Group 8-11 metal base catalysed reaction between an olefinic or aromatic compound respectively and the disubstituted monoborane, the product including a carbon-to-boron bond at the substitution position.
In a further aspect of the invention there is provided a process for the preparation of an aromatic or olefinic boronic acid by hydrolysing the aryl or alkene borate as hereinbefore described using established procedures. The ease of hydrolysis is a function of the disubstituted monoborane used. Some aryl and alkene borates are more amenable to hydrolysis than those derived from pinacolborane.
Some of the aryl and alkene borates and boronic acids are novel and represent a further aspect of the present invention. Some of these novel compounds are as follows:
4-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid,
4-Hydroxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylalanine,
3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid,
3-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid,
5-(4-Phenyl-1,3,2-dioxaborolan-2-yl)-1,3-benzodioxole,
5-(4,5-Dimethyl-1,3,2-dioxaborolan-2-yl)-1,3-benzodioxole,
5-(4,5-Diphenyl-1,3,2-dioxaborolan-2-yl)-1,3-benzodioxole,
5-[4-(Methoxymethyl)-1,3,2-dioxaborolan-2-yl]-1,3-benzodioxole,
5-Tetrahydro-3aH-cyclopenta[d][1,3,2]dioxaborol-2-yl-1,3-benzodioxole,
5-(4,4,6-Trimethyl-1,3,2-dioxaborinan-2-yl)-1,3-benzodioxole,
5-(4,4,6,6-Tetramethyl-1,3,2-dioxaborinan-2-yl)-1,3-benzodioxole,
2-(1,3-Benzodioxol-5-yl)-3-methyl-1,3,2-oxazaborolidine,
2-[(1S,2S,6R,8S)-2,9,9-Trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.02,6]dec-4-yl]benzonitrile,
(1S,2S,6R,8S)-4-(4-Methoxy-2-methylphenyl)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.02,6]decane,
2,6-Dimethoxy-3-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.02,6]dec-4-yl]pyridine,
(1S,2S,6R,8S)-2,9,9-Trimethyl-4-(2,3,4-trimethoxyphenyl)-3,5-dioxa-4-boratricyclo[6.1.1.02,6]decane,
(1S,2S,6R,8S)-4-(2-Methoxyphenyl)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.02,6]decane,
(1S,2S,6R,8S)-2,9,9-Trimethyl-4-[2-(trifluoromethyl)phenyl]-3,5-dioxa-4-boratricyclo[6.1.1.02,6]decane,
(1S,2S,6R,8S)-2,9,9-Trimethyl-4-(2-methylphenyl)-3,5-dioxa-4-boratricyclo[6.1.1.02,6]decane,
2-[(1R,2R,6S,8R)-2,9,9-Trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.02,6]dec-4-yl]benzonitrile,
(1R,2R,6S,8R)-4-(4-Methoxy-2-methylphenyl)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.02,6]decane,
2,6-Dimethoxy-3-[(1R,2R,6S,8R)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.02,6]dec-4-yl]pyridine,
(1R,2R,6S,8R)-2,9,9-Trimethyl-4-(2,3,4-trimethoxyphenyl)-3,5-dioxa-4-boratricyclo[6.1.1.02,6]decane,
(1R,2R,6S,8R)-4-(2-Methoxyphenyl)-2,9,9-trimethyl-3,5-dioxa4-boratricyclo[6.1.1.02,6]decane,
(1R,2R,6S,8R)-2,9,9-Trimethyl-4-[2-(trifluoromethyl)phenyl]-3,5-dioxa-4-boratricyclo[6.1.1.02,6]decane,
(1R,2R,6S,8R)-2,9,9-Trimethyl-4-(2-methylphenyl)-3,5-dioxa-4-boratricyclo [6.1.1.02,6]decane,
2-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenol,
4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenol,
3,4-Dimethoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde,
Ethyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate,
Ethyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate,
1,3-Dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,4(1H,3H)pyrimidinedione,
Ethyl 4-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate,
Methyl 2-(acetylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate,
Phenyl[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanone,
4,4,5,5-Tetramethyl-2-(2,4,6-trimethoxyphenyl)-1,3,2-dioxaborolane,
2-(2-Methoxy-1-naphthyl)-4,4,5,5 tetramethyl-1,3,2-dioxaborolane,
2-(2-Bromophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane,
4,4,5,5-Tetramethyl-2-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,3,2-dioxaborolane,
3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)benzylamine,
4,4,5,5-Tetramethyl-2-(2,3,4,6-tetramethoxyphenyl)-1,3,2-dioxaborolane,
N-[2-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetamide,
2-(6-Methoxy-2-naphthyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane,
2,4-Dimethoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine,
2-(2-Fluoro[1,1xe2x80x2-biphenyl]-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane,
2-(4-Methoxy-1-naphthyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane,
4-[4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,3-thiazol-2-amine,
4,4,5,5-Tetramethyl-2-(4-{[(E)-3-methyl-1-butenyl]oxy}phenyl)-1,3,2-dioxaborolane,
1-[4xe2x80x2-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)[1,1xe2x80x2-biphenyl]-4-yl]-1-ethanone,
3-Bromo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-9H-carbazole,
6-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-2-naphthol,
2-Methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenol,
2-Methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenol,
2,6-Dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol,
5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole,
4,4,5,5-Tetramethyl-2-(4-phenoxyphenyl)-1,3,2-dioxaborolane,
N-[2-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetamide,
Ethyl 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]acetate, and
4-Hydroxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylalanine.
The process according to the present invention is applicable to chemistry on solid polymer support or resin bead in the same manner as conventional chemistry is used in combinatorial chemistry and in the preparation of chemical libraries. Thus a suitably substituted olefinic or aromatic ring compound linked to a polymer surface is reacted with a disubstituted monohydroborane in the presence of a Group 8-11 metal catalyst and a suitable base to form an alkene or aryl borate chemically linked to the polymer surface. This borate may then be reacted with an organic compound having a halogen or halogen-like substituent at a coupling position in the presence of a Group 8-11 metal catalyst and a suitable base to prepare the coupled product chemically linked to the polymer. Excess reactants and by-products may be removed by suitable washing and the coupled product may be isolated by chemically cleaving the link to the polymer. The process is also possible using the alternative strategy where an organic compound having a halogen or halogen-like substituent at a coupling position which is chemically linked to a polymer surface is reacted with an aryl or alkene borate prepared in accordance with the present invention in the presence of a Group 8-11 metal catalyst and a suitable base to form a coupled product linked to the surface of the polymer. Excess reagents and by-products may then be washed away from the surface leaving only the reaction product on the surface. The coupled product may then be isolated by appropriate cleavage of the chemical link from the polymer surface.
It is also possible to prepare polymers by reaction of olefinic or aromatic compounds having more than one boron reactive substituent. Such compounds may be reacted with a disubstituted monohydroborane in the presence of a Group 8-11 metal catalyst and a suitable base to form an aryl or alkene borate having more than one boron functionality. These intermediates may be reacted with organic compounds having more than one halogen or halogen-like substituent to form a polymer. If the olefinic or aromatic ring compound has three or more halogen or halogen-like substituents which react with the disubstituted monohydroborane then it is possible to prepare dendritic molecules in accordance with the process of the present invention.
The olefinic or aromatic ring compound and the organic compound may be separate molecules, or may be linked together such that the aryl or alkene borate formed after reaction with the disubstituted monohydroborane is able to react at a coupling position located elsewhere in the molecule so as to provide for an intramolecular reaction, such as a ring closure reaction.
The process according to the invention is also useful for the preparation of reactive intermediates which, after coupling, take part in further reactions or rearrangements. An example of such an intermediate is one formed by reaction of an ether containing vinylic halide with one of R1, R2 or R3 (formula I) being xe2x80x94OR with a disubstituted monohydroborane. The subsequent coupling of the resulting alkene borate intermediate with an organic compound gives a ketone on hydrolysis of the enol ether.
The following examples are provided to illustrate preferred embodiments of the invention. However it is to be understood that the following description is not to supersede the generality of the invention previously described.